Method and system for controlled automated administration of drugs to patients

ABSTRACT

A method is provided for monitoring a characteristic of a patient, based upon radioactivity, such as the amount of radioactive drug in a patient&#39;&#39;s system, and automatically attaining and maintaining a predetermined level of drug concentration in the patient, based on such monitoring. The system for carrying out such method includes monitoring means for monitoring radioactivity or level of radioactive drug previously administered to a patient, and administering additional radioactive drug to the patient based on such monitoring. The method and system of the invention is particularly applicable to the controlled automated administration of heparin to a patient.

United States Patent 11 1 Gollub METHOD AND SYSTEM FOR CONTROLLED AUTOMATED ADMINISTRATION OF DRUGS TO PATIENTS [76] Inventor: Seymour Gollub, 123 Church St.,

Teaneck, NJ. 07666 [22] Filed: Mar. 14, 1973 [21] Appl. No.: 341,229

[52] US. Cl. l28/l.l, 128/2 A, 128/214 E [51] Int. Cl. A6lb 6/00, A6lm 5/00 [58] Field ofSearch 128/214R,2l4 E,2l3, I

l28/DIG. 12, 1.1, 1.2, 2 A; 250/303 [56] References Cited UNITED STATES PATENTS 2.690.178 9/1954 Bickford 128/213 3,269,386 8/1966 Sherman 128/2 A 3.505.991 4/1970 Hellerstein et a1 l28/l.l 3.598.109 8/1971 Kobayashi et 111...... l28/2.05 F 3.651.806 3/1972 Hirshberg 128/214 E 11181183 8/1972 Viuini ct 111 128/11 X Primary Examiner-Dalton L. Truluck Attorney. Agent, or FirmLerner, David, Littenberg & Samuel [57] ABSTRACT A method is provided for monitoring a characteristic of a patient, based upon radioactivity. such as the amount of radioactive drug in a patients system, and automatically attaining and maintaining a prcdeter mined level of drug concentration in the patient, based on such monitoring. The system for carrying out such method includes monitoring means for monitoring radioactivity or level of radioactive drug previously administered to a patient, and administering additional radioactive drug to the patient based on such monitoring. 7 The method and system of the invention is particularly applicable to the controlled automated administration of heparin to a patient;

21 Claims, 3 Drawing Figures METHOD AND SYSTEM FOR CONTROLLED AUTOMATED ADMINISTRATION OF DRUGS TO PATIENTS FIELD OF THE INVENTION The present invention relates to a method for controlled automated administration of drugs, such as heparin, to mammals based upon the radioactivity of either the drug, the mammals fluids or other body parts, or both.

BACKGROUND OF THE INVENTION Whenever a drug is administered, there is a danger that too little, or too much may be present in certain body components, such as blood, urine, other fluids or tissues. This is particularly true for drugs which require repeated administration, and/or drugs with powerful and potentially hazardous actions. Thus, in many instances, it is essential to attain and maintain a relatively constant level of drug amount or concentration in a particular body part, organ, tissue or fluid. This is especiaally true in the treatment of blood clots or thrombosis employing drug therapy. I

The formation of blood clots in the circulation is a catastrophic event common to a number of crippling and lethal diseases such as heart disease, vascular disease and stroke. The same mechanism intravascular coagulation is a key problem in the application of new techniques aimed at alleviating or preventing impending disaster associated with circulatory problems as in present day surgical practice with prosthetic devices. Thus, the prevention or arrest of clots or thrombosis is a major, widespread, unsolved problem in medicine and surgery today.

Particularly prominent in the treatment of thrombosis is the use of heparin. Undoubtedly, it is the most powerful modality of therapy presently known for prevention of this condition. Unfortunately, proper application of this therapy is difficult to achieve. Even in the most experienced hands, significant variation of blood heparin level occurs. Therefore, significant variation of coagulability takes place. Consequently, the patient is at a satisfactory" level of anticoagulation for short periods of time in transit between high and low levels, as heparin level arises after administration and falls with extravascular distribution and excretion. As a result, the greatest period of time during anticoagulant therapy is spent at levels which are inadequate (and therefore permit intravascular blood clotting) or at levels which are excessive (and therefore may result in hemorrhage).

In large part, this is the result of inadequate and inappropriate laboratory methods of testing for heparin action, e.g., the whole blood clotting time. Present methods for control of heparin therapy are too time consuming and cumbersome for the significant biological variations which occur with this powerful and effective drug. They require multiple injections over short time intervals or continuous intravenous infusion to attempt quate control of therapy. These technical difficulties have often discouraged the use of heparin.

However, if heparin therapy could be substantially controlled such that the proper blood level could be immediately attained and thereafter substantially maintained constant, it is believed that heparin anticoagulation would be more widely and effectively used with consequent decrease or elimination of blood clot formation .in cardiovascular and cerebrovascular disease as well as prosthetic implants and devices.

, The method and system of the invention provide means by which constant precision control of anticoagulant therapy may be easily obtained and automatically maintained by the mere setting of an instrument dial or dials.

BRIEF STATEMENT OF THE INVENTION In accordance with the present invention, there is provided a method for monitoring a characteristic of a patient and automatically administering a substance to the patient based on such monitoring. Such method finds application in the controlled automated administration of drugs to patients and generally comprises administering a radioactive substance to a patient, such as a radiopharmaceutical, monitoring the radioactivity in said patient, such as the radioactivity of either the drug, the patients fluids, organs, tissues, or both the drug and the aforementioned parts of the patient, and automatically administering additional radiopharmaceutical to the patient based on such monitoring. The monitoring step and the step for automatically administering additional radiopharmaceutical to the patient based on such monitoring are coordinated so as-to maintain a predetermined level of radiopharmaceutical concentration in a particular body portion of the patient.

In one embodiment of the method of the invention, the monitoring step comprises sensing the blood stream of the patient for radioactivity, which radioactivity corresponds to the level of radiopharmaceutical concentration which was previously administered; and when the sensed level of radioactivity falls below a predetermined level, automatically activating means for administering additional radiopharmaceutical to the patient, thereby causing the level of radiopharmaceutical to be increased to a desired predetermined level; and when the sensed radioactivity rises above a predetermined level, automatically deactivating said means for administering additional radiopharmaceutical, thereby causing a leveling off of and subsequent fall of concentration of radiopharmaceutical in the patients blood stream to said predetermined level.

In a preferred embodiment of the method of the instant invention, the radiopharmaceutical administered to the patient is a radioactive heparin, such as heparin labeled with 35 It has been found that the measurement of 35,; activity in the blood stream appears to be a measure of blood heparin levels.

Further, in accordance with the present invention, a system is provided for carrying out the aforedescribed method which system comprises, in combination, monitoring means for monitoring radioactivity in a patient and feeding means for automatically administering a therapeutic substance, such as a radiopharmaceutical, to the patient based on such monitoring, said administering means being in operative communication with respect to said monitoring means.

In one embodiment of the system of the invention, the feeding means comprises infusion means, in communication with a supply of radiopharmaceutical, for automatically administering radiopharmaceutical to a patient, and infusion conduit means linking said patient to said infusion means. The monitoring means comprises radioactivity sensing means, afferent fluid conduit means in communication with said sensing means and the patient, for passing a desired fluid from the patient to said sensing means, and control means linked to said sensing means and to said infusion means, for automatically controlling said infusion means based on the radioactivity sensed by said sensing means. Where the sensing means is employed to detect the level of radioactivity in the patients blood stream, the system will I also include efferent conduit means in communication with said sensing means and the patient,'for passing blood from said sensing means back to the patient.

A preferred embodiment of the instant invention will also include means to automatically shut down the infusion means when the level of radioactivity sensed by said sensing means is at or above a predetermined level. Such embodiment may also include signal means in communication with said infusion means and/or said sensing means to notice to attending personnel that the infusion means is shut down and/or the level of radioactivity is at or above a predetermined level.

In yet another embodiment of the system of the invention, the monitoring means comprises a radioactivity sensing element, one end of which includes a sensing tip which is adapted to be placed in communication with a particular portion of the patients body, such as a patients vein, or particular organ or tissue, and the feeding means comprises infusion means in communication with a supply of radiopharmaceutical, infusion conduit means, one end of which is placed in the same body portion of the patient that the sensing tip is positioned, the other end of which is in communication with the infusion means, and also including control means in communication with the sensing element and the infusion means, for automatically controlling the infusion means based on the level of radioactivity sensed by the sensing element. When the sensing tip of the sensing element is inserted in the patients vein, the sensing tip will preferably be inserted up-stream from the point at which said one end of the infusion conduit means is positioned.

The above systems are capable of miniaturization so that they may be substantially supported by the patient without the need for cumbersome apparatus.

Thus, in the above systems, the signal arising from the monitoring means is used to control the rate of addition of radiopharmaceutical to the patient, such that the concentration of radiopharmaceutical in the patient is maintained at a predetermined relatively constant desired level. As indicated, the above systems are particularly applicable to the automatic assessment of blood heparin level, and to use such information to control intravenous heparin infusion rate so as to maintain blood heparin at a predetermined relatively constant level.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. l 'is a diagrammatic representation of a system in accordance with the present invention.

FIG. 2 is a diagrammatic representation of an alternate system in accordance with the present invention.

FIG. 3 is an enlarged view of a portion of the system of the invention shown in FIG. 2.

DETAILED DESCRIPTION OF THE INVENTION FIG. 1 illustrates a preferred embodiment of a system for carrying out the method of the present invention, said system including monitoring means in the form of a radiation detector apparatus 10 and infusion apparatus 12. The patient indicated generally by the numeral 14 is so prepared that some portion, part or area of his body, in the present case, fluid, such as blood, is hooked up to the radiation detector via afferent fluid conduit means 16, one end 18 of which is placed in the patients vein, and the other end 20 of which is connected to the radiation detector. Blood passed from the patient through conduit means 16 to the radiation detector 10 is returned via efferent conduit means 22 to the patient. The radiation detector 10 is in operative communication with infusion means 12 by means of the control conduit 24. The infusion means 12 is connected to the patient via infusion conduit 26.

The radiation detector 10 includes means for sensing radioactivity in the afferent fluid passed from the patient via conduit 16 to the detector 10. In addition, the

radiation detector 10 will be provided with a rate meter, appropriately calibrated for the level of radioactivity to be sensed. The rate meter may be adjusted so that a minimum count rate and a maximum count rate may be designated, which minimum and maximum correspond to the minimum and maximum predetermined levels of radioactivity and, consequently, radioactive drug levels in the patients blood. The radiation detector will also include conventional circuitry which would cause actuation or shut-down of the infusion apparatus 12 depending upon the level of radioactivity sensed by the sensing element of the radiation detector 10.

The infusion apparatus 12 will comprise a conventional infusion device which is actuated by levels of radioactivity sensed by the radiation detector 10 and will administer appropriate volumes of radioactive drug according to the minimum and maximum count rates or predetermined levels of radioactivity. For example, the infusion apparatus 12 may include or be connected to a source of radioactive drug, such as a sterile plug-in" in cartridge of 35 heparin.

The infusion apparatus will be of conventional conrent to the DC motor would control the rate of heparin infusion and this current would be determined by the blood heparin monitoring means or radiation detector 10.

The method of the invention employing the system shown in FIG. 1 is carried out as follows: a pharmaceutical is made radioactive, such as heparin labeled with the beta emitting radioisotope 35 s and a pharmacologic dose of the radioactive heparin is administered to the patient.,The patient will be hooked up to the conduit 26 of the infusion apparatus 12 and the conduits 16 and 22 of the radiation detector 10. Blood flowing from the patient via conduit 16 is constantly monitored for radioactivity by the radiation detector 10. The patients blood (or other body fluid) is constantly perfusing, or flowing through, or flowing past the sensing element of the radiation detector and then, if necessary (as in the case of blood) is returned to the patient's normal blood-flow pattern in his blood stream via conduit 22.

When the level of radioactivity sensed is believed below the designated minimum count rate, the radiation detector 10 does not inhibit operation of the infusion apparatus 12, that is, there is no electrical inhibition or impediment to the infusion apparatus which then delivers the radiopharmaceutical by slow constant infusion to the patient, either by injection, infusion, inhalation, or other means of administration. This tends to raise the level or radiopharmaceutical in the patients body, fluids, tissues and the like.

When the level of radioactivity sensed is above the designated minimum count rate, there is caused, by appropriate conventional electrical circuitry in the radiation detector, a break in the circuit which activates or runs the infusion apparatus, thus inhibiting or stopping the delivery of radiopharmaceutical to the patient. This tends to cause a leveling off and subsequent fall of the concentration or amount of radiopharmaceutical in the patients body, fluids, tissues, etc.

Since the volume of blood flowing from the patient to the radiation detector will be fixed, and since the transit time of blood through the radiation detector will be rapid relative to the rate of change of blood radiopharmaceutical level, there will be no need for blood flow rate metering.

The system of FIG. 1 may be modified to include means for shutting down the infusion apparatus when the level of radioactivity sensed is above a designated maximum count rate. Such means includes independent conventional circuitry and other conventional means to stop the infusion apparatus. Thus, where in those instances there may be a continuing slow rise in level of radiopharmaceutical after attainment ofa minimum level ofradioactivity (due to slow equilibrium rates or other causes) or where there may be a malfunction of any portion of the apparatus, then when the level of radioactivity sensed is above the designated maximum count rate, the infusion apparatus, through said independent circuitry and other conventional means, is caused to shut down. Simultaneously, an alarm may be set in motion consisting of visual and audible signals connected up to such circuitry and other conventional means of said infusion apparatus or radiation detector, consisting of visual and audible signals which will give notice of this situation to attending personnel.

FIGS. 2' and 3 illustrate an alternate embodiment of the system of the present invention which includes a radiation detector 10 and an infusion apparatus 12 as described in FIG. 1, except each may be in miniaturized form. The system shown in FIG. 2 differs from that shown in FIG. 1 in that the radiation detector 10 is miniaturized and is connected to a probe 30 which may be of the semi-conductor type and may be miniaturized. The probe is placed in a patients vein 32 as shown in FIGS. 2 and 3. The probe 30 includes a sensing tip 34.

The infusion apparatus 12 is connected to the patients vein via conduit 26 which is, in this case, positioned downstream of the sensing tip 34 as shown in FIG. 3. The infusion apparatus 12 isconnected via control conduit 24 to radiation detector 10. It will be apparent that probe 30 and conduit 26 connected to radiation detector 10 and the infusion apparatus 12, respectively, can be carried by a single conduit which is injected into the patients vein.

In the embodiment shown in FIG. 2, there is no need for afferent fluid conduits.

The system shown in FIG. 2 operates as follows: A desired amount of radiopharmaceutical, such as radioactive heparin, is administered to the patient. The system ofthe invention is then hooked up to the patient as shown in FIG. 2 and in FIG. 3. Blood radioactivity is sensed by the sensing tip 34 of the probe'30 and is relayed to the radiation detector. 10. Depending upon the level of minimum and maximum count rates selected by the physician and set on the radiation detector and on the actual level of radioactivity sensed by the probe 30, activation or inhibition of the infusion apparatus 12 is caused by the radiation detector. As shown, when the infusion apparatus 12 is actuated and is delivering radiopharmaceutical to the patient, the radiopharmaceutical in this case is delivered downstream of the sensing tip of the probe 30. I

It will be apparent to one skilled in the art that the radiation to be sensed by the radiation detector may be beta or gamma, and the beta may be positron or negatron in nature. Furthermore, the radiation detector, including its internal components and circuitry and rate meter may be of any conventional type suitable to the radionuclide emission to be measured. Furthermore, the infusion apparatus may be of any conventional type.

The drugs which may be administered and automatically controlled in accordance with the present invention can be of any nature as long as they may be made radiopharmaceuticals, or appropriately measured by radiopharmaceuticals related in structure, or function to the drug of interest.

It will also be apparent that the system as-described herein may be employed for organ profusion, tissue profusion, or cell culture maintenance employing the same technique described herein.

What is claimed is:

1. A method for monitoring a characteristic of a patient and automatically administering a substance to the patient based on such monitoring, which comprises administering a radioactive substance to a patient, monitoring the radioactivity in said patient and automatically administering a therapeutic drug to the patient, said administering being directly responsive to said monitoring. 7

2. The method-in accordance with claim 1 wherein said radioactive substance is said therapeutic drug.

3. The method in accordance with claim 2 wherein said radioactive substance is injected into the blood stream of a patient.

4. The method in accordance with claim 2 wherein the step of monitoring theradioactivity in the patient comprises continuously monitoring the blood stream of the patient for radioactivity.

5. The method in accordance with claim 1 wherein said radioactive substance is a radiopharmaceutical.

6. The method in accordance with claim wherein said radiopharmaceutical is radioactive heparin.

7. The method in accordance with claim 1 wherein said monitoring step and said step for automatically administering a therapeutic drug to the patient are coordinated so as to maintain a predetermined level of radioactive drug concentration in a particular body portion of the patient.

8. The method in accordance with claim 7 wherein said monitoring step comprises sensing the blood stream of the patient for radioactivity which corresponds to the level of radioactive drug which was previously administered, and when said sensed radioactivity falls below a predetermined level, automatically activating means for administering additional radioactive drug to the patient thereby causing the level of radioactive drug to be increased to said predetermined level, and when said sensed radioactivity rises above a predetermined level, automatically deactivating said means for administering additional radioactive drug, thereby causing a leveling off of and subsequent fall of concentration of radioactive drug in the patients blood stream to said predetermined level.

I 9. The method in accordance with claim 8 wherein said radioactive drug is radioactive heparin.

10. The method in accordance with claim 9 wherein said radioactive heparin is S tagged heparin.

11. A system for carrying out the method as defined in claim 1, comprising, in combination, monitoring means for monitoring radioactivity in apatient, administering means in operative communication with said monitoring means and responsive to said monitoring means, for automatically administering a therapeutic substance tothe patient, and means responsive to said monitoring means for controlling and activating said administering means.

12. The system in accordance with claim 11 wherein said administering means comprises infusion means, in communication with a supply of radioactive drug, for automatically feeding radioactive drug to a patient, and infusion conduit means linking said patient to said infusion means.

13. The system in accordance withclaim 12, wherein said monitoring means comprises radioactivity sensing means, afferent fluid conduit means in communication with said sensing means and the patient, for passing a desired fluid from the patient to said sensing means, and control means linked to said sensing means and to said infusion means for automatically controlling said infusion means based on the radioactivity sensed by said sensing means.

14. The system in accordance with claim 13 including, in addition, efferent conduit means in communication with said sensing means and the patient, for passing fluid from said sensing means back to said patient.

15. The system in accordance with claim l3including means to automatically shut down said infusion means when the level of radioactivity sensed by said sensing means is at or above a predetermined level.

16. The system in accordancewith claim 15 including signal means in communication with said infusion means and/or said sensing means to notice to attending personnel that said infusion means is shut down and/or the level of radioactivity is at or above a predetermined level.

17. The system in accordance with claim 11 wherein said monitoring means comprises a radioactivity sensing element, one end of which including a sensing tip is adapted to be placed in a patients vein, and said administering means comprises infusion means in communication with a supply of radioactive drug, infusion conduit means, one end of which is placed in a patients vein, the other end of which is in communication with said infusion means, and also including control means in communication with said sensing element and said infusion means, for automatically controlling said infusion means based on the level of radioactivity sensed by said sensing element.

18. The system in accordance with claim 17 wherein said sensing tip of said sensing element is inserted in the patients vein upstream from the point at which said one end of said infusion conduit means.

' 19. The system in accordance with claim 11 wherein said monitoring means and administering means are coordinated so as to maintain a predetermined level of radioactive drug concentration in a particular body portion of thepatient.

20. The system in accordance with claim 12'wherein said infusion means and'said monitoring means are in miniaturized form.

21. The system in accordance with claim 13 wherein said infusion means and said monitoring means are in miniaturized form. 

1. A method for monitoring a characteristic of a patient and automatically administering a substance to the patient based on such monitoring, which comprises administering a radioactive substance to a patient, monitoring the radioactivity in said patient and automatically administering a therapeutic drug to the patient, said administering being directly responsive to said monitoring.
 2. The method in accordance with claim 1 wherein said radioactive substance is said therapeutic drug.
 3. The method in accordance with claim 2 wherein said radioactive substance is injected into the blood stream of a patient.
 4. The method in accordance with claim 2 wherein the step of monitoring the radioactivity in the patient comprises continuously monitoring the blood stream of the patient for radioactivity.
 5. The method in accordance with claim 1 wherein said radioactive substance is a radiopharmaceutical.
 6. The method in accordance with claim 5 wherein said radiopharmaceutical is radioactive heparin.
 7. The method in accordance with claim 1 wherein said monitoring step and said step for automatically administering a therapeutic drug to the patient are coordinated so as to maintain a predetermined level of radioactive drug concentration in a particular body portion of the patient.
 8. The method in accordance with claim 7 wherein said monitoring step comprises sensing the blood stream of the patient for radioactivity which corresponds to the level of radioactive drug which was previously administered, and when said sensed radioactivity falls below a predetermined level, automatically activating means for administering additional radioactive drug to the patient thereby causing the level of radioactive drug to be increased to said predetermined level, and when said sensed radioactivity rises above a predetermined level, automatically deactivating said means for administering additional radioactive drug, thereby causing a leveling off of and subsequent fall of concentration of radioactive drug in the patient''s blood stream to said predetermined level.
 9. The method in accordance with claim 8 wherein said radioactive drug is radioactive heparin.
 10. The method in accordance with claim 9 wherein said radioactive heparin is S35 tagged heparin.
 11. A system for carrying out the method as defined in claim 1, comprising, in combination, monitoring means for monitoring radioactivity in a patient, administering means in operative communication with said monitoring means and responsive to said monitoring means, for automatically administering a therapeutic substance to the patient, and means responsive to said monitoring means for controlling and activating said administering means.
 12. The system in accordance with claim 11 wherein said administering means comprises infusion means, in communication with a supply of radioactive drug, for automatically feeding radioactive drug to a patient, and infusion conduit means linking said patient to said infusion means.
 13. The system in accordance with claim 12, wherein said monitoring means comprises radioactivity sensing means, afferent fluid conduit means in communication with said sensing means and the patient, for passing a desired fluid from the patient to said sensing means, and control means linked to said sensing means and to said infusion means for automatically controlling said infusion means based on the radioactivity sensed by said sensing means.
 14. The system in accordance with claim 13 including, in addiTion, efferent conduit means in communication with said sensing means and the patient, for passing fluid from said sensing means back to said patient.
 15. The system in accordance with claim 13 including means to automatically shut down said infusion means when the level of radioactivity sensed by said sensing means is at or above a predetermined level.
 16. The system in accordance with claim 15 including signal means in communication with said infusion means and/or said sensing means to notice to attending personnel that said infusion means is shut down and/or the level of radioactivity is at or above a predetermined level.
 17. The system in accordance with claim 11 wherein said monitoring means comprises a radioactivity sensing element, one end of which including a sensing tip is adapted to be placed in a patient''s vein, and said administering means comprises infusion means in communication with a supply of radioactive drug, infusion conduit means, one end of which is placed in a patient''s vein, the other end of which is in communication with said infusion means, and also including control means in communication with said sensing element and said infusion means, for automatically controlling said infusion means based on the level of radioactivity sensed by said sensing element.
 18. The system in accordance with claim 17 wherein said sensing tip of said sensing element is inserted in the patient''s vein upstream from the point at which said one end of said infusion conduit means.
 19. The system in accordance with claim 11 wherein said monitoring means and administering means are coordinated so as to maintain a predetermined level of radioactive drug concentration in a particular body portion of the patient.
 20. The system in accordance with claim 12 wherein said infusion means and said monitoring means are in miniaturized form.
 21. The system in accordance with claim 13 wherein said infusion means and said monitoring means are in miniaturized form. 